INSERM, Neurocentre Magendie, U1215, Bordeaux, France.
University of Bordeaux, Neurocentre Magendie, U1215, Bordeaux, France.
Neuropsychopharmacology. 2018 Feb;43(3):492-502. doi: 10.1038/npp.2017.149. Epub 2017 Jul 19.
In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BK channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BK channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BK as a potentially relevant molecular target for the development of drug medication against FXS/ASD.
在脆性 X 综合征 (FXS) 中，人们认为感觉过敏和习惯形成障碍导致注意力过载，并对环境特征的过度和残留显著性产生各种行为异常反应，而这些特征通常会被忽略。这种现象被称为感觉防御，被认为是多动症、过度兴奋和对常规变化的负面反应的潜在原因，这些反应通常对 FXS 患者有害。然而，缺乏操纵感觉过敏的工具使得无法进行实验测试来评估这一假设的相关性。最近的工作表明，BK 通道激动剂 BMS-204352 可有效逆转 FXS 的 Fmr1-KO 小鼠模型中的皮质过度兴奋性和相关感觉过敏。在本研究中，我们报告说，将 Fmr1-KO 小鼠暴露于新的或不熟悉的环境中会导致多种行为异常，例如多动、筑巢和背部过度梳理。用 BK 通道激动剂 BMS-204352 逆转感觉过敏可防止 Fmr1-KO 小鼠出现这些行为异常。这些结果支持感觉防御假说，并证实 BK 作为一种潜在相关的分子靶点，可用于开发治疗 FXS/ASD 的药物。
